credence to a model in which adipose tissue is
required for fasting-induced increases in plasma
uridine.

The liver is widely held to be the major organmaintaining plasma uridine supply (4). However,even though fasting triggered increases in plas-ma uridine, we found that the genes responsiblefor de novo uridine synthesis were all down-regulated by fasting in the liver (Fig. 7C). In con-trast, Cad, which encodes the rate-limiting enzymefor uridine biosynthesis, was highly expressedin three different adipose tissue depots when ex-amined under both fed and fasted conditions(Fig. 7D). Furthermore, the genes encoding theother two enzymes in the uridine biosyntheticpathway, Dhodh and Umps, manifested expres-sion patterns similar to Cad (fig. S2). This suggeststhat adipose tissue is indeed an important site ofuridine synthesis contributing to fasting-inducedrises in plasma uridine. Consistent with this, biopsyspecimens of subcutaneous fat from subjects de-picted in Fig. 1C uniformly harbored reduced uri-dine content in the postprandial state (Fig. 7E).To explore further the role of adipose tissuein plasma uridine homeostasis, we studied astreptozotocin (STZ)–induced model of type 1 dia-betes. As expected, STZ administration causedhyperglycemia (Fig. 7F) and a rapid loss of fatmass (fig. S3). After the initial loss of body mass,mice subsequently reached a plateau of bodyweight that was maintained for the subsequent7 weeks (Fig. 7G). Under these conditions, bothplasma and bile uridine levels were reduced tohalf the levels observed in the control vehicle-treated group (Fig. 7H). Similarly, uridine con-centrations in both brown adipose tissue (BAT)and the heart were reduced (Fig. 7I). In contrast,uridine levels in livers isolated from STZ-treatedmice were comparable to those in the controlgroup (Fig. 7I), which suggests that uridine bio-synthesis in the liver remains functional even inthe absence of circulating insulin. However, theseemingly unaltered production of uridine inthe liver is insufficient to maintain normal levelsof plasma uridine under fasting conditions.Although our observations support the ideathat adipose tissue plays a critical role in plasmauridine homeostasis, the inducible and constitu-tive loss of adipose tissue as well as lowering ofsystemic insulin production through the loss ofDeng et al., Science 355, eaaf5375 (2017) 17 March 2017 5 of 9

Fig. 6. Thermoregulation effects of enteral administration of uridine. (A) Body temperature of
male WT (chow or HFD for 10 weeks) and age-matched ob/ob mice was monitored before and after
oral administration of uridine (1 g/kg, n = 6 per group). (B and C) Body temperature of male WT
(HFD for 10 weeks) or age-matched ob/ob mice was monitored before and after oral administration
of glucose or glucose-uridine solution (n = 6 per group). Data were analyzed by two-way ANOVA and
no significant difference was detected between each group. Error bars denote SEM.